Prostacyclin analogues are known to exhibit therapeutic effects related to inhibition of platelet aggregation, lesions inhibition, reduction in gastric secretion, bronchodilation etc. Treprostinil (1) and its pharmaceutically acceptable salts, chemically known as (1R,2R,3aS,9aS)-[[2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-[(3 S)-3-hydroxyoctyl]-1H-benz[f]inden-5-yl]oxy]acetic acid, is a stable synthetic analogue of prostacyclin (PGI2), belonging to the benzindene prostacyclin class of compounds. USFDA approved formulations such as Remodulin (infusion), Tyvaso (for inhalation) have Treprostinil (1) and its pharmaceutically acceptable salts, as the active ingredient for inducing vasodilation during the treatment of pulmonary arterial hypertension.

The synthesis of Treprostinil (1) was first disclosed in U.S. Pat. No. 4,306,075 and since then different synthetic strategies for this molecule have been disclosed in various patents such as U.S. Pat. Nos. 6,441,245, 6,528,688, 6,700,025, 6,765,117, 6,809,223, 8,242,305 etc. The scheme for method of synthesis as disclosed in U.S. Pat. No. 6,765,117 is given below.

Most of the synthetic methods described in the aforementioned references resort to expensive, hazardous reagents and tedious condensation, deprotection and separation procedures at various intermediate stages of synthesis. For example, U.S. Pat. No. 6,441,245 discloses deprotection of alkyl-protected phenolic hydroxyl group in treprostinil using n-butyl lithium and diphenyl phosphine. These hazardous reagents require stringent anhydrous conditions and pose operational difficulties, especially when used on industrial scales.
WO2016055819 discloses a process wherein the C5H11 side chain is added in the later stage of synthetic sequence. The process comprises condensation of aldehyde and alkyne derivatives, followed by subsequent reactions to give the tricyclic intermediate and further reactions including Wittig reaction, stereoselective carbonyl reduction, deprotection etc. for the introduction of C5H11 side chain.
Various protecting functionalities for the phenolic hydroxyl group have been disclosed in prior art. However, the inventors observed that considering the complex, multi-step synthetic sequence, highly acid-labile, bulky protecting groups such as triphenylmethyl (trityl) were not feasible on a commercial scale. Also, use of protecting agents such as tertiary butyldimethylsilyl (TBDMS) for the phenolic hydroxyl either necessitated very specific reagents like tetra n-butyl ammonium fluoride (TBAF) or high pressure hydrogenation conditions for deprotection.
Hence, there was a need for a practical and economical synthetic process for Treprostinil which comprised use of appropriate, easily removable hydroxyl protecting groups that would decrease the level of associated impurities in the reactions. Deprotection of the hydroxyl group could be done at appropriate stages with mild and selective reagents to achieve the desired conversions. It was found that reactions of phenolic hydroxyl substrates protected with unsaturated alkyl like allyl, crotyl, propargyl had a better impurity profile as compared to other protecting groups as the reactions were facile, provided higher yields and the impurities were below the usual limits. Also, the intermediate products with unsaturated alkyl as protecting group that were isolated had a better impurity profile and did not require any further purification, thus avoiding additional steps and lowering the overall costs.
The present inventors have developed an efficient and economical process for synthesis of Treprostinil (1) and its pharmaceutically acceptable salts, overcoming the problems faced in the prior art, by utilizing alkyl or unsaturated alkyl groups as protecting agents for the phenolic hydroxyl group. The use of appropriate hydroxyl protecting groups like alkyls, allyl, crotyl, MEM and selective deprotecting reagents like tetrakis triphenylphosphine palladium, aluminium chloride/decanethiol, helped in controlling the impurity formation at various intermediate stages and provided the desired molecule with significant improvement in yield.